MICROTUBULES IN TESTICULAR TOXICITY OF CARBENDAZIM

多菌灵睾丸毒性中的微管

基本信息

批准号：
6055938
负责人：
MARION G MILLER
金额：
$ 21.9万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6055938
关键词：
antifungal agents benzimidazoles environmental toxicology intermediate filaments laboratory mouse laboratory rat male microtubules pesticide biological effect pesticide residues testis disorder toxin metabolism vimentin

项目摘要

DESCRIPTION (Adapted from the Investigator's Abstract): Benomyl and its metabolite carbendazim are benzimidazole fungicides which cause testicular toxicity in rats at dose levels where no other organ system is affected. A recent study has supplied strong evidence that carbenazim (CBZ), and not benomyl, is responsible for testicular damage. Histopathologically, testicular toxicity after CBZ administration is characterized by a stage specific sloughing of the seminiferous epithelium. CBZ is known to inhibit microtubule assembly but the relationship of this to the cellular events which underlie sloughing is not known. The hypothesis central to the present proposal is that the singular sensitivity of the testis to CBZ toxicity is the result of disruption of a specific microtubule associated protein (MAP)/tubulin interaction only found in the testis with resultant loss of microtubule assembly and decreased phosphorylation of MAP or tubulin protein(s). A model is presented which addresses the role of testis microtubule vs. intermediate filament structures in the stage specific sloughing induced by CBZ. The first specific aim is to establish that the effect of CBZ on microtubule assembly is specific for testis microtubule assembly and involves disruption of a testis specific MAP-tubulin interaction. The second specific aim is to identify the MAP/tubulin testis-specific proteins which are affected by CBZ and address the possibility that CBZ induced changes in protein phosphorylation play a role in cytoskeletal collapse. The final specific aim will determine the relationship to sloughing of early cytoskeletal changes induced by CBZ administered at dose levels both above and below the sloughing threshold in normal rats and vim-knockout mice. Preliminary immunocytochemical data has indicated that, concomitant with loss of microtubule structure, intermediate filaments collapse towards the basal membrane. A model is proposed which explains the stage specific effects of CBZ in terms of the function of microtubules and intermediate filaments at different stages of germ cell development. The vimentin-knockout mouse provides an excellent experimental model for testing the role of intermediate filaments in the sloughing events which follow CBZ administration.

描述（改编自调查人员的摘要）：代谢物甲bendazim是苯咪唑杀菌剂，引起睾丸在不影响其他器官系统的剂量水平的大鼠中毒性。一个最近的研究提供了有力的证据，表明Carbenazim（CBZ），而不是贝诺基负责睾丸损伤。组织病理学， CBZ给药后的睾丸毒性以一个阶段为特征植物上皮的特异性链条。 CBZ已知会抑制微管组装，但它与细胞事件的关系尚不清楚哪个基础。该假设的中心目前的建议是睾丸对CBZ的奇异灵敏度毒性是特定微管相关的破坏的结果蛋白质（地图）/微管蛋白相互作用仅在睾丸中发现微管组装的损失和MAP或微管蛋白的磷酸化降低蛋白质。提出了一个模型，以解决睾丸的作用微管与阶段特异性的中间丝结构 CBZ诱导的链条。第一个具体目的是确定 CBZ对微管组装的影响特异于睾丸微管组装并涉及睾丸特异性地图管蛋白的破坏相互作用。第二个特定目的是识别地图/微管蛋白受CBZ影响并解决的睾丸特异性蛋白质 CBZ诱导蛋白质磷酸化的变化起作用的可能性起作用在细胞骨架塌陷中。最终的具体目的将决定与CBZ诱导的早期细胞骨架变化的链条的关系以剂量级别的剂量施用正常的大鼠和VIM敲除小鼠。初步免疫细胞化学数据具有表明，与微管结构丧失同时，中间细丝向基底膜塌陷。提出了一个模型解释了CBZ在功能方面的特定阶段效应微管和中间丝在不同阶段的生殖细胞发展。波形蛋白敲除鼠标提供了出色的实验测试中间细丝在链条事件中的作用的模型跟随CBZ给药。